Human inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, constitutes a major health problem in developed countries. Ulcerative colitis exhibits a characteristic profile of chronic inflammation involving the distal colon and rectum, and is generally recognized as an immune-mediated disorder resulting from abnormal interaction between colonic microflora and mucosal immune cells. Excessive inflammatory and immune responses in the intestine are thought to be due to a breach in the epithelial barrier in the gut that segregates commensal microflora from the host's systemic organs. Indeed, deterioration of the mucus layer of the colon is prominent in patients with ulcerative colitis. In addition, studies in rodents have linked tissue damage and disruption of the epithelial barrier in the gut to cytokine imbalances. The production of these inflammatory mediators has been implicated in the pathogenesis of experimental colitis, IBD and colorectal cancer in humans. The gastrointestinal tract is constantly exposed to bacteria and microbial products that are recognized by innate immune receptors such as the Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Thus, defects in the innate immune system are associated with the development of colonic inflammation. Recent studies indeed, revealed that mutations in two of the NLR family members NOD2 and cryopyrin/NLRP3 are associated with a high risk for developing Crohn's disease. The focus of this proposal is to study the role of NLRs and their adaptor proteins in the development of intestinal inflammation and related diseases. Results from our laboratory and others demonstrated that the NLRs are pivotal to the activation of the innate immune response to enteroinvasive pathogens such as Salmonella, Shigella and Listeria and drive the activation of NF-:B, MAPK and caspase-1 signaling pathways. Our preliminary data also show that a subgroup of NLR family members mediate the induction and release of proinflammatory mediators and protect against colits. Altogether, the goal of this proposal is to define the precise role of NLR signaling in intestinal inflammation and colon carcinogenesis. The proposed project will provide novel and important information that will help to elucidate the role of NLRs in inflammation, the pathogenesis of IBD and host-commensal interactions. PUBLIC HEALTH RELEVANCE: Innate immune system has been suggested to mediate the development of intestinal inflammation and gastroinstestinal carconogenesis (GIC). Nonetheless, the role of distinct innate immune signaling pathways in the development of inflammation and GIC is yet to be unraveled. The proposed studies will contribute to our insight into the molecular mechanisms by which the innate immune system participates in colitis/carcinogenesis and might create new therapeutic options for inflammatory diseases.